1. Field of the Invention
This invention relates to an agent for relieving lipotoxicity.
2. Description of the Related Art
Adipocyte is a cell which is specialized in storing a large amount of free fatty acid as neutral fat, and cells other than adipocyte (nonadipocyte) are incapable of storing such a large amount of neutral fat. In the adipocyte, neutral fat is decomposed into diacylglycerol and a free fatty acid either continuously or in response to the particular stimulus. Although a free fatty acid is a hemolysin toxin which is insoluble in water, it becomes soluble and non-toxic by binding to albumin, and the fatty acid-albumin complex is carried to liver where it is consumed. When the fatty acid-albumin complex enters the liver, the fatty acid is quickly incorporated by the liver, and only the albumin returns to the blood. The free fatty acid caused by degradation is re-esterified by the action of insulin. As a consequence of such mechanism, concentration of the free fatty acid in plasma is maintained under normal conditions within a certain range.
However, when a large amount of free fatty acid is continuously present in the plasma (hyper-free fatty acidemia) for some reasons, for example, by continuous lipolysis under the reduced action of insulin, dysfunction of nonadipocyte of liver, heart, pancreas, kidney, skeletal muscle, and the like is sometimes generated by the re-distribution of the free fatty acid, and this dysfunction is called “lipotoxicity”.
When the nonadipocyte is pancreatic β-cell, the lipotoxicity is known to induce apoptosis and impairment of glucose-stimulated insulin secretion. More specifically, there has been reported that palmitic acid induces β-cell apoptosis, decrease β-cell prolification, and impairment of glucose-stimulated insulin secretion of the cultivated pancreatic β-cell, and stearic acid induces apoptosis of the cultivated pancreatic β-cell (see, for example, Non-patent documents 1 to 3).
The decrease of the glucose-stimulated insulin secretion in the pancreatic β-cell results in the increase of blood glucose level.
It has also been known that chronic high blood glucose level higher than the normal level may result in the dysfunction of the pancreatic β-cell, and this dysfunction is called glucotoxicity. More specifically, this glucotoxicity is known to induce increase in glucose sensitivity of the pancreatic β-cell to invite excessive secretion of the insulin, and this results in the exhaustion of the pancreatic β-cell and decrease of the glucose-stimulated insulin secretion. Decrease in the number of the pancreatic β-cell is also known to occur (see, for example, Non-patent document 2).
This results in the vicious circle that the increase in the blood glucose level caused by the lipotoxicity induces the glucotoxicity while decrease in the insulin action induces the lipotoxicity, and this vicious circle promotes progress from abnormal glucose tolerance to diabetes in the patients of abnormal glucose tolerance, as well as worsening of the conditions in the diabetes patients.
In the experiments carried out by using rat and human cultivated pancreatic β-cells, some fatty acids, for example, palmitoleic acid (an ω7 fatty acid containing 16 carbon atoms and having a degree of unsaturation of 1), oleic acid (an ω9 fatty acid containing 18 carbon atoms and having a degree of unsaturation of 1), and linoleic acid (an ω6 fatty acid containing 18 carbon atoms and having a degree of unsaturation of 2) have been reported to exhibit action of preventing lipotoxicity and glucotoxicity.
It has also been disclosed that, β-cell apoptosis, decrease β-cell prolification, and suppression of the glucose-stimulated insulin secretion of the pancreatic β-cell are counteracted by preliminary addition of palmitoleic acid to the lipotoxicity induced by palmitic acid (a saturated fatty acid) in the Langerhans cell of rat pancreas (see, for example, Non-patent document 1).
Similarly, there is a disclosure that β-cell apoptosis, decrease β-cell prolification, and suppression of the glucose-stimulated insulin secretion of the cultivated pancreatic β-cell are counteracted by preliminary addition of palmitoleic acid or oleic acid to the lipotoxicity induced by palmitic acid and/or glucotoxicity induced by glucose in the Langerhans cell of human pancreas (see, for example, Non-patent document 2).
It has also been disclosed that apoptosis of the pancreatic β-cell was suppressed by the preliminary addition of palmitoleic acid, oleic acid, or linoleic acid to the lipotoxicity induced by palmitic acid in the cultivated Langerhans cell of human and rat pancreas (see, for example, Non-patent document 3).
In the meanwhile, oleic acid has also been reported to induce decrease of the glucose-stimulated insulin secretion in rat cultivated pancreatic β-cell to further induce the lipotoxicity (see, for example, Non-patent document 4). These publications disclose results of experiments carried out by using cultivated cells on the action of several fatty acids in preventing the lipotoxicity and/or the glucotoxicity. However, these results include contradictory results as in the case of oleic acid, and the situation is not necessarily clear. In addition, there is no disclosure indicative of the in vivo action, the relieving action, or a substance having both the preventive and relieving actions.
Thiazolidine derivatives are known to have the action of protecting the nonadipocyte by accumulating the free fatty acid in the adipocyte, and biguanide drugs are known to normalize sugar usage and oxidation in the pancreatic β-cell which had been damaged by the lipotoxicity. Nicotinamide and aminoguanidine which are inhibitors of inducible nitric oxide synthase (iNOS) have been indicated to have the possibility of suppressing the apoptosis induced by the lipotoxicity. These drugs, however, are known to have side effects. As described above, there is so far no clinically acceptable drug that has the action of relieving the lipotoxicity, and hence, the action of relieving the glucotoxicity, as well as the reduced side effects.    Non-patent document 1: Maedler, K. et al., Diabetes, 2001, vol. 50, pp. 69-76    Non-patent document 2: Maedler, K. et al., Diabetes, 2003, vol. 52, pp. 726-733    Non-patent document 3: Eitel, K., Biochemical and Biophysical Research Communications, 2002, vol. 299, pp.    Non-patent document 4: Busch, A. N. et al., Diabetes, 2002, vol. 51, pp. 977-987